Olive, David L.
Unexplained infertility is a phenomenon commonly encountered in the modern reproductive endocrinology and infertility practice. It often proves frustrating to the patient in that there is no specific, identifiable problem at which treatment can be directed. Instead, a number of empiric therapies have been developed to treat these couples . Among such treatments is the use of oral ovulation-induction drugs.
Empiric treatment with clomiphene citrate and, more recently, letrozole, has been a popular first-line approach with many gynecologists, reproductive endocrinologists, and even family physicians. However, recent recommendations have discouraged this practice. The Cochrane Collaboration, in a 2010 systematic review and meta-analysis, states that ‘there is no evidence of clinical benefit of clomiphene citrate for unexplained infertility’ . Similarly, a 2013 Committee Opinion from the American Society for Reproductive Medicine (ASRM) states that on the basis of available evidence, empiric use of clomiphene with intercourse in the treatment of unexplained infertility is no better than expectant management and should be discouraged .
These recommendations, although originating from well respected sources, are wrong! The reasons why they are incorrect illustrate problems and limitations of many randomized trials and systematic reviews. When designing a high-quality study, it is important to ask and then answer the correct question. It is also imperative to have an adequate sample size. Finally, it is essential to completely delve into and analyze existing data versus taking simple outcome measures at face value.
The editorial will closely examine the existing data and illustrate why oral ovulation induction medications, even in the absence of intrauterine insemination (IUI), are of value in the treatment of unexplained infertility. I will also provide conditions which appear to be necessary to achieve this efficacy, as well as a blueprint for future studies to address this topic.
The reason for subfertility in the patient with unexplained infertility is, by definition, unknown. Nevertheless, a treatment plan to enhance their ability to conceive must be designed and implemented. Today's therapeutic approaches have been based upon the knowledge that many patients with unexplained infertility are able to achieve pregnancy, albeit at a low monthly fecundity rate. The task for the treating physician is thus to try and compress time, to enhance the monthly chance of conception and thus speed up the pregnancy that would likely occur if time was not a factor.
This leads to three different strategies that have been employed to attack this diagnosis: produce multiple ovulations, arrange for more sperm to reach the oocyte, or both of these simultaneously. Multiple ovulations in a given cycle should improve the chances that a pregnancy will occur in that month rather than necessitating many months; several such cycles may avoid years of frustration and possibly the detriment of aging oocytes. Placing sperm in greater numbers in the vicinity of the oocyte should enhance the chance that a sperm capable of penetrating and fertilizing is available for this process. Combining the two should further improve the success rates.
In using ovulation induction medications in the anovulatory patient, monofollicular development is a desirable goal. The reasoning is simple: when the only barrier to conception is ovulation, correcting it with multiple ovulation may well result in multiple pregnancy. This is not so with unexplained infertility: such patients already ovulate each cycle and have failed to conceive. The goal is to enhance their chances by providing multiple chances in a given cycle. In treating such women, producing mono-ovulation is in fact no treatment at all! Some clinicians have expressed concerns regarding the enhanced risk of multiple (and high-order) gestation. However, this concern seems unfounded. Although multiple gestation is a definite risk in ovulation induction of multiple follicles in the couple suffering from chronic anovulation, the risk in the patient with unexplained infertility appears greatly reduced. Imagine a woman with unexplained infertility of 2 years duration: she has had 24 ovulations with no success; her chances of suddenly achieving pregnancy with 2 of 2 (or even 3 of 3) is not a very favorable wager!
Given that multiple ovulation is a goal of treatment in unexplained infertility, an intervention must first meet that goal before it can even be considered as a viable option. This is a basic principle in clinical medicine: first set a therapeutic goal, treat to achieve that goal, then once the goal is met assess the outcome. This principle should not be lost during clinical trials.
Currently, available studies have uniformly employed protocols with fixed doses of drug for a predefined amount of time. Predicted number of ovulations as assessed by ultrasonography is not used. Nor do any protocols include the potential for escalating treatment dosage until multiple follicular response is demonstrated. In other words, the standard protocol among the randomized controlled trials (RCTs) in this area utilizes a fixed-dose regimen for the intervention rather than a fixed goal. Conversely, clinical practice is much more likely to use the latter.
The Cochrane Collaboration systematic review and meta-analysis looked only at randomized trials comparing the use of clomiphene to placebo or no treatment for unexplained infertility . The primary outcome measures were live birth and multiple pregnancy rates, both assessed via intention-to-treat analysis. The secondary outcomes included ongoing pregnancy, clinical pregnancy, ectopic pregnancy, and miscarriage rates. Seven studies were identified and analyzed. No differences were seen between those treated with clomiphene citrate and those not so treated. However, the review does not assess the validity of the comparison by determining the goal (and the achievement of the goal) in the studies cited. Was the treatment with clomiphene designed to produce multiple ovulation? If so, was it achieved among those treated? This is nowhere to be found in the review, yet it represents a critical aspect of this issue.
The ASRM Committee Opinion addresses this issue briefly, and then proceeds to ignore it. The primary article cited by the committee, a randomized trial of 387 women, has an acknowledged goal of monofollicular development with clomiphene treatment . Moreover, patients with more than two potential ovulations were cancelled. It is no great surprise that the study failed to demonstrate efficacy under this protocol.
A handful of studies have examined the use of clomiphene citrate versus no treatment/placebo in patients with unexplained infertility. The first was by the Canadian Unexplained Infertility Study group . In this randomized trial, patients were allocated to either clomiphene treatment or placebo for 4 months. The stated goal was to achieve multiple ovulations in each treatment cycle, and to achieve this, the study dose was 100 mg daily for 5 days. However, the medication was given on cycle days 5–9 (less than optimal for multiple ovulation) and no ultrasound examinations were performed to insure or even tabulate the rate of multiple follicular development. Nonetheless, over 4 months of treatment, the clomiphene group had a pregnancy rate of 19%, whereas there were no pregnancies in the control group.
In 1998, Guzick et al. examined 45 cohort studies that had evaluated treatments for unexplained infertility. From their systematic review, they concluded that the adjusted monthly pregnancy rate with expectant management in 11 published investigations was 1.3–4.1%. In the three studies in which clomiphene was used without IUI in the treatment of unexplained infertility, the adjusted cycle pregnancy rate was 5.6%. This represents an increase over the rate seen with expectant management of 35–331%! Unfortunately, none of these studies provide information as to the occurrence of multiple follicular development in the treated women.
Finally, in 2008, Bhattacharya et al. published the above-mentioned randomized trial comparing treatment with clomiphene citrate to expectant management . The stated goal was to achieve mono-ovulation, and to this end, the dose of clomiphene employed was only 50 mg/day. If three or more follicles were detected by ultrasonography, the cycle was cancelled and the dosage subsequently decreased. As might be expected, the pregnancy rate did not differ between the groups. The report does not state how many women had two ovulations or provide the mean number of large follicles at the time of ultrasound examination.
Although coupled with IUI treatments, there are some data that suggest multiple follicular development with clomiphene will enhance pregnancy rates in unexplained infertility. Deaton et al. compared clomiphene 50 mg/day during days 5–9 of the cycle with a single late follicular ultrasound and human chorionic gonadotropin triggering of ovulation, followed by an IUI, to use of ovulation monitoring and timed intercourse. As they performed an ultrasound examination in all treatment cycles, they were able to correlate the number of large follicles with the outcome. In 93 cycles, there was a single predicted ovulation and six resulted in pregnancy, for a rate of 6.45%. When two or more follicles developed, there were eight pregnancies in 55 cycles for a pregnancy rate of 14.55%! Importantly, there were no multiple births during the study.
Although limited data exist comparing clomiphene to no treatment, there are no data comparing letrozole to placebo or expectant management. However, a number of reports have compared letrozole to clomiphene in this population, with results showing equivalent  or increased pregnancy rates  with letrozole. Moreover, one study has looked at follicle number as it correlates with letrozole treatment . By increasing the dose of letrozole from 5 to 7.5 mg/day, the cycle pregnancy rate increased from 4.3 to 6.5%, which is not a significant difference given the sample size, but nevertheless a 51% increase.
Letrozole may also pose a better alternative in that clomiphene often produces an adverse effect upon the endometrium, necessitating estradiol supplementation following the time of clomiphene administration to optimize pregnancy rates [11,12]. Of course, none of the above trials examined the endometrial thickness or quality, and none supplemented with estradiol. Letrozole, conversely, does not generally have this effect, even in high doses , and seems to enhance endometrial receptivity compared to clomiphene .
The existing information on the value of clomiphene and letrozole in the treatment of unexplained infertility is sparse and poor, making conclusive recommendations difficult. However, to say that the treatment is of no value or should be discouraged smacks of hyperbole. It also ignores the information currently available, inadequate as it may be, that oral ovulation induction drugs can be of value in the treatment of unexplained infertility if employed properly.
The data do suggest that clomiphene (and perhaps letrozole), when used in the manner of most primary care physicians and gynecologists, is not effective. Simply handing the patient a prescription in the hope that it will produce multiple follicular growth and increased chances of pregnancy appears to be an ineffective strategy. To effectively use these medications in the unexplained infertility population, a treatment goal of multiple ovulation should be initially established, the treatment should be monitored via ultrasonography to insure more than one large follicle has developed, the endometrium should be evaluated via ultrasonography to determine if supplemental estradiol is needed, and if the treatment goal is not met, increasing the dosage of medication in the next cycle is indicated.
Similarly, future studies addressing this important and relevant issue should follow similar principles. Fixed-dose protocols do not address the issue at hand. Fixed-goal protocols should be initiated, with escalating doses, until the goal is reached. Ultrasonography should be employed in all patients to assess follicular number and size, as well as endometrial development. Outcome should be compared in those cycles achieving the follicular goal versus no treatment or those with inadequate response.
Unexplained infertility is an everyday diagnosis in most infertility practices. Whereas many expensive, time-consuming treatments of known efficacy are available, it is of significant value to our patient population to have, as a first-line therapy, a simple, inexpensive approach. However, optimizing this treatment will insure that there is value in the approach rather than simply delaying an inevitable progression to more complex therapy.
Conflicts of interest
The author has no conflicts of interest to declare.
1. Fritz MA, Speroff L. Clinical gynecologic endocrinology and infertility. 8th ed Philadelphia:Lippincott Williams and Wilkins; 2011 .
2. Hughes E, Brown J, Collins JJ, Vanderkerchove P. Clomiphene citrate for unexplained subfertility in women. Cochrane Database Syst Rev. 2010; CD000057
3. Practice Committee of the American Society for Reproductive Medicine Use of clomiphene citrate in infertile women: a committee opinion. Fertil Steril. 2013; 100:341–348.
4. Bhattacharya S, Harrild K, Mollison J, et al. Clomifene citrate or unstimulated intrauterine insemination compared with expectant management for unexplained infertility: pragmatic randomized controlled trial. Br Med J. 2008; 337:a716
5. Fisch P, Casper RF, Brown SE, et al. Unexplained infertility: evaluation of treatment with clomiphene citrate and human chorionic gonadotropin. Fertil Steril. 1989; 51:828–833.
6. Guzick DS, Sullivan MW, Adamson GD, et al. Efficacy of treatment for unexplained infertility. Fertil Steril. 1998; 70:207–213.
7. Deaton JL, Gibson M, Blackmer KM, et al. A randomized, controlled trial of clomiphene citrate and intrauterine insemination in couples with unexplained infertility or surgically corrected endometriosis. Fertil Steril. 1990; 54:1083–1088.
8. Badawy A, Shokeir T, Allam AF, Abdelhady H. Pregnancy outcome after ovulation induction with aromatase inhibitors or clomiphene citrate in unexplained infertility. Acta Obstet Gynecol. 2009; 88:187–191.
9. Ibrahim MI, Moustafa RA, Abdel-Azeem AA. Letrozole versus clomiphene citrate for superovulation in Egyptian women with unexplained infertility: a randomized, controlled trial. Arch Gynecol Obstet. 2012; 286:1581–1587.
10. Badawy A, Metwally M, Fawzy M. Randomized controlled trial of three doses of letrozole for ovulation induction in patients with unexplained infertility. Reprod Biomed Online. 2007; 14:559–562.
11. Yagel S, Ben-Chetrit A, Anteby E, et al. The effect of ethinyl estradiol on endometrial thickness and uterine volume during ovulation induction by clomiphene citrate. Fertil Steril. 1992; 57:33–36.
12. Gerli S, Gholami H, Manna C, et al. Use of ethinyl estradiol to reverse the antiestrogenic effects of clomiphene citrate in patients undergoing intrauterine insemination: a comparative, randomized study. Fertil Steril. 2000; 73:85–89.
13. Pritts EA, Yuen AK, Sharma S, et al. The use of high dose letrozole in ovulation induction and controlled ovarian hyperstimulation. ISRN Obstet Gynecol. 2011; 2011:242864
14. Ganesh A, Chauhan N, Das S, et al. Endometrial receptivity markers in infertile women stimulated with letrozole compared with clomiphene citrate and natural cycles. Syst Biol Reprod Med. 2014; 60:105–111.